* = Presenting author
Ferslew B.*1, Sherman C.2, Nguyen D.3, Graham R.1
1Theravance Biopharma, Clinical Pharmacology and DMPK, South San Francisco, United States 2Theravance Biopharma, Biostatistics, South San Francisco, United States 3Theravance Biopharma, Clinical Development, South San Francisco, United States
TD-1473 is a novel, intestine-restricted, pan-Janus kinase (JAK) inhibitor being developed for the treatment of inflammatory bowel diseases (IBD), including ulcerative colitis (UC). JAK inhibition has demonstrated efficacy for inducing remission in UC patients using a systemically active oral agent (tofacitinib), but its use is associated with a risk of serious systemic adverse effects. TD-1473 was designed to inhibit JAK in the gastrointestinal tract following oral dosing while minimizing systemic exposure and associated adverse events. This double-blind, placebo-controlled, dose-escalation study in healthy subjects was conducted to evaluate the safety, tolerability, and PK after single and multiple oral doses of TD-1473.
Healthy male and female subjects (n=8 per cohort) were randomized to receive TD-1473 or placebo (3:1 ratio) for each cohort in the single ascending dose (SAD, 10 to 1000mg) or the 14-day multiple ascending dose (MAD, 10 to 300mg) parts of the study. Safety and tolerability were assessed by monitoring treatment-emergent adverse events (TEAEs), electrocardiograms (ECGs), vital signs, and laboratory parameters. PK was assessed in plasma and urine.
No moderate, severe, or serious TEAEs were reported in subjects administered TD-1473; no TEAEs led to study discontinuation. TEAEs incidence in the SAD was 33% (10/30) for TD-1473 and 40% (4/10) for placebo. TEAEs incidence in the MAD was 58% (14/24) for TD-1473 and 88% (7/8) for placebo. No clinically meaningful treatment-related effects on vital signs, clinical laboratory, or ECG parameters were observed.
TD-1473 was eliminated in a multiphasic manner with mean terminal elimination half-life values ranging from 4.40 to 43.88 hrs. Median Tmax values ranged between 0.51 to 2.00 hrs. Systemic TD-1473 exposures were low; Cmax and AUC0–24 increased in a dose-proportional manner with minimal accumulation as assessed on Day 14 (Cmax and AUC0–24 accumulation ratios from Day 1 to Day 14 ranged from 0.52 to 2.27 and 1.36 to 1.63, respectively). Steady-state was achieved after 7 to 9 days of dosing. Mean steady-state apparent clearance (CL/F) and volume of distribution (V/F) ranged between 5519 to 8662 L/hr and 113500 to 571300 L, respectively. The fraction of the dose excreted as unchanged TD-1473 in urine through 24 hours after single and multiple doses of TD-1473 was <0.500%.
TD-1473 exhibits low systemic concentrations (consistent with intestine restriction) with dose-proportional PK following single (up to 1000mg) and multiple doses (up to 300 mg). TD-1473 was generally well tolerated in this study. Results are supportive of further development of TD-1473 for the treatment of IBD, including UC.